Cellular Signalling by Lipoproteins in Cultured Smooth Muscle Cells from Spontaneously Hypertensive Rats

Abstract

We investigated pivotal signalling responses of cultured aortic smooth muscle cells (VSMC) from the spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto rat (WKY) to lipoproteins. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL₃) stimulated a time- and dose-dependent accumulation of inositol phosphates in VSMC. SHR and WKY VSMC exhibited comparable half-maximal dose requirements (≈13 µg/ml for LDL and ≈14 µg/ml for HDL₃), although, at any given dose, the response of SHR VSMC was significantly greater than WKY VSMC. Simultaneous addition of LDL and HDL₃ to VSMC resulted in additive stimulatory effects on phosphoinositide catabolism. Pertussis toxin pretreatment of VSMC completely negated the stimulatory effects of LDL and HDL₃ on IP accumulation. [³²P]-ADP ribosylation and immunoblotting studies revealed the guanine nucleotide-binding (G protein) substrate(s) for pertussis toxin to be a G_i protein(s). SHR and WKY VSMC did not differ with respect to levels of G_iα or G_β, and, thus, the amplified responsiveness in SHR VSMC cannot be attributed to alterations in levels of pertussis toxin-sensitive G protein. The spectrum of signalling responses elicited by LDL and HDL₃ are similar to those elicited by vasoactive hormones, and thus lipoproteins may, via stimulation of phosphoinositide catabolism, ⁴⁵Ca²⁺ uptake and Na⁺/H⁺-exchange, directly regulate smooth muscle cell growth and contraction.

Experimental and interventional dietary study in humans on the role of HDL fatty acid composition in PGI2 release and Cox‐2 expression by VSMC

“…Arachidonic acid signalled through similar pathways than HDL: pertussis toxin‐sensitive G proteins, p42/44MAPK, p38MAPK and JNK‐1. Some of these pathways have previously been involved in the activation of different cell types by both HDL [4,35–37] and AA [38–41]; however, this is the first study in which these pathways are analyzed in relation to the effect of AA on PGI 2 release and Cox‐2 expression in human VSMCs. G protein‐coupled receptors and p42/44MAPK, two pathways that are functionally connected [42,43], seem to be key on both PGI 2 release and Cox‐2 up‐regulation by AA.…”

Abnormalities of membrane function and lipid metabolism in hypertension A review

“…216,217 The cellular signaling elicited by LDL is enhanced in cultured VSMC of SHR. 158 In contrast to human platelets, Na ϩ /H ϩ exchanger activity in rat VSMC is stimulated not only by LDL but also by HDL 3 , resulting in a similar pH i rise in both cases. 158 Thus, in rat VSMC, both lipoprotein fractions enhance Ca 2ϩ influx and augment Na ϩ /H ϩ exchanger activity.…”

“…158 In contrast to human platelets, Na ϩ /H ϩ exchanger activity in rat VSMC is stimulated not only by LDL but also by HDL 3 , resulting in a similar pH i rise in both cases. 158 Thus, in rat VSMC, both lipoprotein fractions enhance Ca 2ϩ influx and augment Na ϩ /H ϩ exchanger activity. The regulation of pH i in platelets of Dahl rats is also dependent on plasma lipids.…”

“…157 It is important to mention that Ca 2ϩ influx in cultured rat VSMC is augmented not only by LDL but also by HDL 3 , the extent of cell signaling elicited by both lipoprotein fractions being almost identical. 158 This could explain a cosegregation of BP with these two lipoprotein fractions in Lyon F 2 hybrids. 153 Cell Ca 2ϩ handling is also associated with plasma or membrane lipids in humans.…”

Sex Hormones Affect the Calcium Signaling Response of Human Arterial Cells to LDL

“…In contrast, testosterone resulted in an increased response of [Ca /2 ] i to N-LDL and Ox-LDL in LDL has since been shown to increase intracellular signaling activity through the inositol phosphate sys-both EC and SMC. While this did not achieve statistical significance except at the lower concentrations of Oxtem, resulting in a marked increase in cytosolic free calcium [33,34]. This occurs in a dose-related fashion LDL in the EC, a consistent and significant elevation of [Ca /2 ] i was seen in the SMC.…”